Several surveys of centenarians from Eurasia have revealed that specific mitochondrial DNA (mtDNA) lineages are associated with reduced neurodegenerative disease and increased longevity. These same Eurasia mtDNA lineages (haplogroups) show striking regional localization which we have recently discovered is the result of mtDNA missense mutations that permitted the founders of these lineages to adapt to the increasingly colder climates as they migrated out of Africa into Eurasia and then into Siberia and North America. We hypothesize that missense mutations are protective of neurodegenerative diseases and aging because they partially uncouple mitochondrial oxidative phosporylation (OXPHOS). This increased heat production, but it is protective of aging because it keeps the electron transport chain oxidized thus reducing mitochondrial reactive oxygen (ROS) species production and oxidative damage. To test this hypothesis, we propose to determine if Native American mtDNA acquired new adaptive mutations as they migrated southward from the arctic to tropical South America. We will also correlate skeletal muscle mitochondrial OXPHOS enzyme levels with mtDNA haplogroups and correlate the biochemical defects with alterations in muscle energetics as assessed by magnetic resonance and Near Infra-red spectroscopy. Then transfer the various mtDNA haplogroups into the same ?o lymphoblastoid cell nuclear background and test the resulting cybrids for differences in mitochondrial enzymes, OXPHOS coupling, ROS production, mitochondrial and cellular oxidative damage, hyper-activation of the mitochondrial permeability transition pore (mtPTP) and changes in MITOCHIP gene expression profile. We will determine the extent of somatic mtDNA control region (CR) and rearrangement mutations that accumulate in the cells and tissues of subjects with different climatic adaptive mutations. Finally, we will sequence the mtDNAs of mice that have adapted to climatic extremes. If they also harbor adaptive mtDNA mutations, then use female ES cell line to introduce the variant mtDNA lineages into the mouse germ line. These mice will be bred the progeny tested for their sensitivity to heat and cold, the biochemistry and physiology of their mitochondria, their exercise physiology, and their longevity. [unreadable] [unreadable]